title: Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.
abstract: Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques.
authors.affiliation: Laboratory Animal Medicine, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, United States.
authors.forename: Alida
authors.initials: A
authors.lastname: Ault
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Tennant
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Gorres
authors.forename: Michael
authors.initials: M
authors.lastname: Eckhaus
authors.forename: Netanya G
authors.initials: NG
authors.lastname: Sandler
authors.forename: Annelys
authors.initials: A
authors.lastname: Roque
authors.forename: Sofie
authors.initials: S
authors.lastname: Livio
authors.forename: Saran
authors.initials: S
authors.lastname: Bao
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Foulds
authors.forename: Shing-Fen
authors.initials: SF
authors.lastname: Kao
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Patrick
authors.initials: P
authors.lastname: Schmidlein
authors.forename: Mary Adetinuke
authors.initials: MA
authors.lastname: Boyd
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Pasetti
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Rao
mesh_terms: D000818:Animals; D057138:Bacterial Shedding; D060085:Coinfection; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D005517:Foodborne Diseases / Q000382:microbiology / Q000517:prevention & control; D056724:Immunity, Humoral; D016867:Immunocompromised Host; D007413:Intestinal Mucosa / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008070:Lipopolysaccharides / Q000097:blood; D008253:Macaca mulatta; D012481:Salmonella Infections, Animal / Q000150:complications / Q000276:immunology / Q000517:prevention & control*; D022562:Salmonella Vaccines / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000382:microbiology*; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D022562:Salmonella Vaccines; D014613:Vaccines, Attenuated
keywords: Human immunodeficiency virus; Live oral vaccine; Nonhuman primates; Nontyphoidal Salmonella; Simian immunodeficiency virus